Antisense oligonucleotides can hybridize with viral mRNA and inhibit translation or processing of mRNA, thereby inhibiting viral replication. Hybridization of antisense oligonucleotides to viral mRNA (antisense:mRNA) occurs by hydrogen bonding between complementary nucleotides present on an antisense oligonucleotide and viral mRNA. Adenine (A) is complementary to thymidine (T) and uracil (U), while cytosine (C) is complementary to guanine (G). Along the antisense:mRNA chain classical base pairs AU, TA or UA, GC, or CG are present. Additionally, some mismatched base pairs (e.g., AG, GU) may be present.
The ability to form hydrogen bonds between nucleotides enables antisense oligonucleotides to be targeted to specific viral nucleic acid sequences. Thus, antisense oligonucleotides can be targeted to nucleic acid sequences present only in viral nucleic acid, and viral gene expression can be selectively inhibited.
Oligonucleotides have been claimed as anti-viral agents able to hybridize with viral nucleic acid. For example, Tullis, U.S. Pat. No. 5,023,243 provides a general description of use of antisense oligonucleotides. Kaji, U.S. Pat. No. 4,689,320, provides data showing a decrease in mortality in mice infected with Herpes Simplex Virus when treated with an antisense oligonucleotide having a nucleotide sequence targeted to Herpes Simplex Virus. Goodchild et al., U.S. Pat. No. 4,806,463, provide data to demonstrate the ability of several different specified antisense oligonucleotides to inhibit HTLV-III (HIV) replication, and gene expression in cultured cells infected with HIV. Cantin et al., U.S. Pat. No. 5,110,802, describe the use of a particular methylphosphonate linked oligonucleotide to inhibit HIV replication. Ecker, U.S. Pat. No. 5,166,195, provides data showing the inhibition of a cloned tat gene using certain antisense oligonucleotides (these U.S. patents are hereby incorporated by reference herein). Matsukura et al., Proc. Natl. Acad. 86:4244, describe the inhibition of HIV expression in a chronically infected cell without killing the host cell using a phosphorothioate linked oligonucleotide targeted to a rev sequence.
In addition to inhibiting viruses by an antisense mechanism, oligonucleotides can inhibit viruses in a sequence non-specific mechanism. For example, Majumdar et al., Biochemistry 28:1340 (1989) describe the use of phosphorothioate oligonucleotides to inhibit HIV reverse transcriptase.